Tumorigenesis inp27/p53- andp18/p53-double null mice: Functional collaboration between the pRb and p53 pathways

Abstract

Mice lacking both p18(Ink4c) and p27(Kip1) develop a tumor spectrum similar to pRb(+/-) mice, and loss of p53 function accelerates tumorigenesis in pRb(+/-) mice. We hypothesized that codeletion of either p18 or p27 in conjunction with p53 deletion will also accelerate tumorigenesis. Mice lacking both p18 and p53 develop several tumors not reported in either single null genotype, including hepatocellular carcinoma, testicular choriocarcinoma, hemangiosarcoma, leiomyosarcoma, fibrosarcoma, and osteosarcoma. Mice lacking both p27 and p53 exhibit a decreased lifespan and develop unique tumors, including papillary carcinoma of the colon, hemangiosarcoma, and leiomyosarcoma. In both p18/p53 and p27/p53 double null genotypes, the incidence and spectra of tissues that develop lymphoma are also increased, as compared to the single null genotypes. The development of p27/p53 double null colon tumors correlates with secondary changes in cell-cycle protein expression and CDK (cyclin-dependent kinase) activity, perhaps contributing to the progression of colorectal cancer. We concluded that p18 and p27 can, not only functionally collaborate with one another, but also can independently collaborate with p53 to modulate the cell cycle and suppress tumorigenesis in a tissue-specific manner.

Combined loss of p21waf1/cip1 and p27kip1 enhances tumorigenesis in mice

“…27 Therefore, there are multiple evidences for the role that either p21 or p27 has in tumorigenesis, alone or in combination with other tumor suppressors and oncogenes. 14,[28][29][30][31] In addition, CDK-independent functions have been described for p21 and p27, highlighting their role as oncogenes or in cellular stress in different tissues, implicating p21 and p27 as possible therapeutic targets in some processes. 32,33 Up to now, no studies have been described using a doublenull murine model for p21 and p27.…”

Repression of Ah receptor and induction of transforming growth factor-β genes in DEN-induced mouse liver tumors

“…Because of their role as tumor suppressors, the members of the two families of CDK inhibitors, the INK4 (p16, p15, p18 and p19) and the CIP/KIP (p21, p27 and p57) are often found in a silenced state in tumors of many different origins (Damo, Snyder, and Franklin 2005;); however, recent evidence in pancreatic and lung tumors shows up-regulation, rather than repression of p18 (Cdkn2c) and argues against a pure tumor suppressor role for this gene (Joshi et al, 2007;Lindberg, Akerstrom, and Westin, 2007;Pei et al, 2007), whereas p19/ARF (Cdkn2d) is almost exclusively repressed in tumors (Lowe and Sherr, 2003;Canepa et al, 2007). Our results are consistent with those findings, showing increased expression of Cdkn2c in both RB-positive and RB-negative tumors, and decreased expression of Cdkn2d in RB-positive but not in RB-negative tumors.…”

MicroRNA-802 Promotes Osteosarcoma Cell Proliferation by Targeting p27

“…Numerous studies have identified p27 as a key tumor suppressor in multiple tumors (Micel et al, 2013). In animal models, loss of p27 is associated with infrequent spontaneous pituitary tumors and intestinal adenomas (Damo et al, 2005). Importantly, decreases in p27 protein expression have been found in 60% of human carcinomas, and are associated in breast cancer with poor prognosis (Zhang et al, 2013).…”